A novel 177Lu-labeled porphyrin for possible use in targeted tumor therapy

Porphyrin and its derivatives exhibit inherent affinity for localization in tumors. Hence, porphyrin derivatives radiolabeled with suitable therapeutic radionuclides could be envisaged as potential agents for targeted tumor therapy. In this direction, a water-soluble porphyrin derivative, viz., 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin was synthesized in-house and radiolabeled with (177)Lu with an aim to prepare an agent for targeted tumor therapy. (177)Lu is an attractive radionuclide for the development of targeted radiotherapeutic agents owing to its suitable decay characteristics [T(1/2)=6.73 d, E(beta(max))=0.49 MeV, Egamma=208 keV (11%)], comparatively longer half-life and ease of production with high specific activity.

(177)Lu was produced by irradiation of enriched Lu(2)O(3) (64.3% (176)Lu) at a thermal neutron flux of 1x10(14) n/cm(2).s for 14 d. The porphyrin was coupled to a suitable chelator, namely, p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid for complexation with (177)Lu. The radiolabeling was achieved by incubating 50 microg of the conjugate with (177)LuCl(3) (200 ng Lu) in acetate buffer (pH approximately 5) at 50 degrees C for 1 h. The radiolabeled conjugate was characterized by high-performance liquid chromatography and its biological efficacy was studied in Swiss mice bearing fibrosarcoma tumors.

(177)Lu was obtained with a specific activity of approximately 550 TBq/g and radionuclidic purity of 99.98%. The (177)Lu-labeled porphyrin conjugate was obtained with 99% radiochemical purity and it exhibited good in vitro stability. Biodistribution studies revealed good tumor uptake (2.01% IA/g) within 3 h post injection (p.i.) with >94% injected activity exhibiting renal clearance. No significant accumulation of activity was observed in any of the vital organs/tissue. The tumor/blood and tumor/muscle ratios were 2.89 and 16.80, respectively, at 3 h p.i. and further increased till 2 days p.i. up to which the studies continued. Serial scintigraphic images recorded using a gamma camera exhibited significant accumulation of activity in tumor over background at 3 days p.i., and the activity was observed to be retained in the tumor till 14 d. Preliminary efficacy studies carried out in Swiss mice bearing fibrosarcoma tumors showed significant regression of the tumor growth in the treated animals.

Bioevaluation and preliminary tumor regression studies provide supportive evidences toward the possible potential of the (177)Lu-labeled porphyrin for targeted tumor therapy.